Title of Invention

"A PROCESS FOR THE PREPRATION OF NOVEL SUBTITUTED 1,2,4-TROIXANES USEFUL AS ANTIMALARIAL AGENTS"

Abstract TITLE OF THE ABSTRACT A process for the preparation of novel substituted 1,2,4-trioxanes useful as antimalarial agents A process for the preparation of novel substituted 1,2,4-trioxanes useful as antimalarial agents by reacting aryl methyl kenone with haloacetate such as ethylbromoacetate or ethylchloroacetate and Zn in presence of catalytic amount of l2 in an aprotic solvent at a temperature ranging from room temperature to refluxing temperature to give p-hydroxyester, dehydrating the above said p-hydroxyester using a dehydrating catalyst in an aprotic solvent at a temperature ranging from room temperature to refluxing temperature to give a,p-unsaturated ester, reducing the above said ester with a metal hydride in an ether solvent at a temperature ranging from 0°C to refluxing to obtain allylic alcohol, photoxygenating the above said allylic alcohol in presence of a sensitizer in an organic solvent at a temperature ranging from -10°C to room temperatures to obtain p-hydroxyhydroperoxide with an aldehyde/ketone, in presence of an acid catalyst in an aprotic organic solvent at a temperature ranging from 0°C to room temperature, isolating and purifying by known methods to furnish novel substituted 1,2,4-trioxanes.
Full Text This invention relates to a process for the preparation of novel substituted 1,2,4-trioxanes useful as antimalarial agents.
This invention particularly relates to preparation of 6-[(substituted biphenyl)vinyl]-1,2,4-trioxanes, a new series of antimalarial agents. More particularly the present invention provides preparation of 1,2,4-trioxanes of general formula 7 wherein X represents hydrogen, halo groups selected from bromo, chloro R1 and R2 represent hydrogen, alkyl group selected from methyl, ethyl, propyl and decyl, aryl group selected from phenyl, or part of a cyclic system such as cyclopentane, cyclohexane, substituted cyclohexane, cyclo(2.2.1)heptane, adamantane. These trioxanes are novel compounds and are useful as antimalarial agents. Some of these compounds have been tested against multi-drug resistant malaria in mice and have shown promising antimalarial activity. The invention, thus relates to pharmaceutical industry.
The trioxanes of the general formula 7 are new chemical entities and they have not been prepared earlier.
The main objective of the present invention is to provide a process for the preparation of novel substituted 1,2,4-trioxanes useful as antimalarial agents.
Accordingly, the present invention provides a process for the preparation of novel substituted 1,2,4-trioxanes useful as antimalarial agents of general formula 7 of the drawing accompanying the specification wherein X repreents hydrogen, halo groups selected from bromo and chloro, R1 and R2 represent hydrogen alkyl groups such as methyl, ethyl, propyl, decyl, aryl selected from phenyl or R1f R2 together represent part of a cyclic system such as cyclopentane, cyclohexane, substituted cyclohexanes, bicyclo (2.2.1) heptane, adamantane which comprises reacting aryl methyl kenone of formula 1 of the drawing accompanying the specification wherein X represents hydrogen, halo groups selected from bromo or chloro with haloacetate such as ethylbromoacetate or ethylchloroacetate and Zn in presence of catalytic amount of l2 in an aprotic solvent at a temperature ranging from room temperature to refluxing temperature to give p-hydroxyester of formula 2 of the drawing accompanying the specification wherein X has the same meaning as above, dehydrating the above said p-hydroxyester using a dehydrating catalyst in an aprotic
solvent at a temperature ranging from room temperature to refluxing temperature to give a,p-unsaturated ester of the formula 3 of the drawing accompanying the specification wherein X has the same meaning as above, reducing the above said ester with a metal hydride in an ether solvent at a temperature ranging from 0°C to refluxing to obtain allylic alcohol of formula 4 of the drawing accompanying the specification wherein X has the same meaning as above, photoxygenating the above said allylic alcohol in presence of a sensitizer in an organic solvent such as herein described at a temperature ranging from -10°C to room temperatures to obtain p-hydroxyhydroperoxide of the formula 5 of the drawing accompanying the specification with an aldehyde/ketone of the general formula 6 of the drawing accompanying the specification wherein R1 and R2 represent hydrogen, alkyl group such as methyl, ethyl, propyl and decyl, aryl selected from phenyl, and part of a cyclic system selected from group consisting of cyclopentane, cyclohexane, bicyclo (2.2.1) heptane, adamantane, in presence of an acid catalyst in an aprotic organic solvent at a temperature ranging from 0°C to room temperature, isolating and purifying by known methods to furnish novel substituted 1,2,4-trioxanes.
In the process aryl methyl ketone of formula 1 of the drawing accompanying the specification are reacted with haloacetate such as ethyl bromoacetate or ethyl chloroacetate and Zn in presence of catalytic amount of I2 in an aprotic organic solvent such as benzene, toluene, diethyl ether, tetrahydrofuran to furnish p-hydroxy ester of formula 2.
These p-hydroxy ester of formula 2 of the drawing accompanying the specification can be isolated and purified by standard laboratory methods such as column chromatography or can be used without purification in the next step, p-hydroxy ester of formula 2 where X=Br, CI are new compounds and they have not been prepared earlier. Hydroxy ester of formula 2 where X=H is a known compound [Farmaco. Ed. Sci 1978,33(12),992-8 (Ital)].
In the process dehydration of p-hydroxy ester of formula 2 of the drawing accompanying the specification may be effected in aprotic organic solvent such as benzene, toluene, CHCI3 in the presence of a dehydrating agent selected from l2, P2O5 p-toluene sulfonic acid, H2S04 or Amberlyst-15 (cation exchanger) to furnish α,ß-
unsaturated esters of formula 3. These unsaturated esters can be isolated and punned by standard laboratory methods such as column chromatography using silica gel as an adsorbent and hexane/ethyl acetate as eluant. The α.ß-unsaturated ester of formula 3 where X=Br. CI are new compounds and they have not been prepared earlier. The α. ß-unsaturated ester of formula 3 where X=H is a known compound [ Chemical Abstract. 1976, 86: P106177d].
In the process reduction of a, ß-unsaturated ester of formula 3 is effected with a complex metal hydride such as UAIH4 in an ether solvent such as diethyl ether, tetrahydrofuran, to furnish allylic alcohol of the formula 4. These allylic alcohol of formula 4 can be isolated and purified by standard laboratory methods such as crystallization or column chromatography on silica gel. The allylic alcohol of formula 4 are new compounds and they have not been prepared earlier.
In the process photooxygenation of allylic alcohol of formula 4 may be effected by passing oxygen gas or air in the solution of the alcohol in an organic solvent and in the presence of a dye and a light source which provides visible light for a period in the range of 2 :o 5 h, to furnish ß-hydroxyhydroperoxide of formula 5. These P-hydroxyhydroperoxide for formula 5 which are new chemical entities can be isolated and purified by standard laboratory methods such as crystallization or column chromatography or can be used in situ, without purification, in the next step. The dye which acts as a sensitizer i.e. converts 302 to highly reactive 'O2. may be selected from methylene blue, Rose Bengal, tetraphenylporphine and the like. Organic solvent used may be selected from CH2CI2, benzene, CH3CN, acetone, ethanol and the like.
In the process reaction of P-hydroxyhydroperoxide of formula 5 with aldehyde/ketones of formula 6 is done in an aprotic solvent in the presence of an acid catalyst to furnish tnoxanes of formula 7. The aldehyde and ketones used may be such as benzaldehyde, acetone, ethyl methyl ketone, methyl propyl ketone, decyl methyl ketone, cyclopentanone, cyclohexanone, bicyclic ketone such as norcamphor and tricyclic ketones such as 2-adamantanone. The acid catalyst used may be selected from HC1, p-toluenesulfonic acid, H2SO4, acidic resin like Amberlyst-15. The aprotic solvents used may be selected from CH2CI2, CHCI3, benzene, CH3CN. These tnoxanes of formula 7 can be isolated and purified by standard laboratory methods such as column chromatography and crystallization. These tnoxanes are new chemical entities and they have not been prepared earlier. Some of the tnoxanes of formula 7 have been tested against malarial parasites in mice and show promising antimalarial activity.In our copending patent application nf-159/02 ,we have claimed a process for preparation of novel tnoxanes
The invention is further illustrated by the following examples which should not, however, be construed to limit the scope of the present invention.
EXAMPLE 1 ETHYL 3-HYDROXY-3-([l,l'-BIPHENYL]-4YL)-BUTANOATE (COMPOUND 2a, FORMULA 2, X =H)
To a refluxing mixture of 4-acetylbiphenyl (20 g), I2 (5 mg) and Zn (6.8 g) in benzene (200 ml) was added ethylbromoacetate (12 ml) dropwise during 30 minutes. The mixture was refluxed for 1 h and then cooled to room temperature. It was acidified with 10% HC1 (100 ml) and benzene layer was separated out. The organic layer was washed with water, dried (Na2S04) and concentrated. The crude product was purified by column chromatography on silica gel to give 20.6g (72.1% yield) of ethyl 3-hydroxy-3-([l,l'-Biphenyl]-4yl) butanoate (2a, formula 2, X=H) m.p. 58-60°C.
The above compound was also prepared using different reaction condition. Table 1 gives the condition used and yield of compound 2a.
TABLE 1

(Table Removed)
The compound 2a was also prepared using ethylchloroacetate under same reaction conditions to
furnish 17.8% yield of ethyl 3-hydroxy-3-([l,l'-Biphenyl]-4yl) butanoate (2a).
ETHYL 3-([l,l -BIPHENYL]-4YL)-BUT-2-ENOATE (COMPOUND 3a, FORMULA 3, X =
H)
To a solution of ethyl 3-hydroxy-3-([l,l-Biphenyl]-4yl)-butanoate (2a, llg) in benzene (250 ml) was added phosphorus pentoxide (4g) and refluxed for 3 h. The benzene layer was decanted and then concentrated. The crude product was purified by column chromatography on silica gel to furnish llg (57.3% yield) of ethyl 3-([l,l-Biphenyl]-4yl)-but-2-enoate (3a, formula 3, X = H) m.p. 76-78°C.
The compound 3a was also prepared using different reaction condition. Table 2 gives the conditions used and the yield of compound 3a.
TABLE 2

(Table Removed)
3-([l,l -BIPHENYL]-4YL)-2-BUTENOL (COMPOUND 4a, FORMULA 4, X = H)
To an ice cooled slurry of LiAlH4 (4.0g) in dry ether (400 ml) was added ethyl 3-([l,l-Biphenyl]-but-2-enoate (3a, 1 lg) in dry ether (200ml) dropwise. The mixture was stirred at 0°C for 2h. The reaction mixture was quenched with water (10 ml). A solution of 10% NaOH (5 ml) was added, stirred and then ether layer was decanted. The precipitate was washed with ether and combined ether extracts were concentrated. The crude product was purified by chromatography on silica gel to give 7.2 g (77.4% yield) of 3-([l,l'-Biphenyl]-4yl)-2-butenol (4a, formula 4, X=H), m.p. 112-114°C.
LiAlFL* reduction of ethyl 3-([l,l -Biphenyl]-but-2-enoate (3a) using THF as solvent under similar conditions furnished 40.6% yield of 3-([l,l -Biphenyl]-4yl)-2-butenol (4a). 3-([l,l-BIPHENYL]-4YL)-l-HYDROXY-BUT-3-EN-2-HYDROPEROXIDE (COMPOUND 5a, FORMULA 5, X = H)
A solution of 3-([l,l-Biphenyl]-4yl)-2-butenol (4a, 200 mg) and methylene blue (2 mg) in acetonitrile (15 ml) was irradiated with 250 watt tungston - halogen lamp at -6°C while oxygen was passed through the reaction mixture. After 4h the reaction mixture was concentrated. The hydroperoxide precipitated out was filtered through a cintered crucible to-furnish 80 mg of hydroperoxide. Mother liquor was purified by column chromatography to furnish 40 mg of hydroperoxide. The combined yield of hydroperoxide (compound 5a, formula 5, X = H) was 120 mg (54.5% yield) m.p. 124°C.
Phototoxygenation of 3-([l,l'-Biphenyl]-4yl)-2-butenol (4a) in CHCI3 at 0° using tetraphenylporphine as sensetizer furnished the above 5a in 81.8% yield.
6-I([l,l-BIPHENYL]-4YL)VINYLl-3-PHENYL-l,2,4-TRIOXANE (TRIOXANE 7aa. FORMULA 7, X=H, R,,R2 = H. Ph).
To a solution of 3-([l.l-Biphenyi]-4yl)-l-hydroxy-but-3-en-2-hydroperoxide (5a. 400 mg) and Benzaldehyde (350 mg) in acetonitrile (10 mi) was added p-toluene sulfonic acid (20 mgj and was stirred at r.t. for 2 h. The reaction mixture was worked up as above and concentrated. Crude product was purified by column chromatography to furnish 280 mg (70% yield) of tnoxane 7aa m.p. 110-112°C.
EXAMPLE 2 8-[([l,l-BIPHENYL]-4YL)VINYL]-6,7,10-TRIOXASPIRO (4,5) DECANE (TRIOXANE 7ab, FORMULA 7, X=H, R,R2 =-CH2CH2CH2CH2-)
To a solution of 3-([l,l-Biphenyl]-4yl)-l-hydroxy-but-3-en-2-hydroperoxide (5a, 430 mg) and cyclopentanone (700 mg) in acetonitrile (10 ml) was added p-toluene sulfonic acid (30 mg) and the reaction mixture was stirred at r.t. for 3 h. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography followed by crystallization from hexane to furnish 250 mg (45.1% yield) of trioxane 7ab. m.p. 102-104°C.
EXAMPLE 3 3-[([l,l-BIPHENYL]-4YL)VINYL]-l,2,5-TRIOXASPIRO (5,5) UNDECANE (TRIOXANE 7ac, FORMULA 7, X=H, R,R2 =-CH2CH2CH2CH2CH2-)
To a solution of 3-([l,l-Biphenyl]-4yl)-l-hydroxy-but-3-en-2-hydroperoxide (5a, 600 mg) and cyclohexanone (1 ml) in acetonitrile (20 ml) was added p-toluene sulfonic acid (20 mg) and the reaction mixture was stirred at r.t. for 1 h. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography followed by crystallization from hexane to furnish 360 mg (46.1% yield) of trioxane 7ac. m.p. 96-98°C.
EXAMPLE 4 3-DECYL-3-METHYL-6-[([l,l-BIPHENYL]-4-YL)-VINYL]-l,2,4-TRIOXANE (TRIOXANE 7ad, FORMULA 7, X =H; R,, R2=CH3, -CH2(CH2)8CH3)
A solution of 3-([l,l -Biphenyl]-4yl)-2-butenol (4a, 200 mg) and methylene blue (2 mg) in acetonitrile (10 ml) and chloroform (10 ml)was photooxygenated at 0°C for 3 h. 2-Dodecanone (0.5 ml) and hydrochloric acid (2 drops) were added and reaction mixture of left at r.t. for 18 h. The reaction mixture was worked up and concentrated. Crude product was purified by column
chromatography on silica gel to furnish l00mg (27% yield, based on allylic alcohol, 4a. used) of tnoxane 7ad m.p. 86-90°C.
EXAMPLE 5 TRIOXANE 8a, FORMULA 8, X = H
A solution of 3-([l,l -Biphenyl]-4yl)-2-butenol (4a, 200 mg) and methylene blue (2 mg) in acetonitrile (15 ml) was photooxygenated at -10°C for 3 h. Norcamphor (250 mg) and p-toluene sulfonic acid (30 mg) were added and reaction mixture of left at r.t. for 18 h. The reaction mixture was worked up and concentrated. Crude product was purified by column chromatography on silica gel to furnish 140 mg (45.1% yield, based on allylic alcohol, 4a, used) of trioxane 8a m.p. 86-90°C.
EXAMPLE 6 TRIOXANE 9a, FORMULA 9, X = H
To a solution of 3-([l,l-Biphenyl]-4yl)-l-hydroxy-but-3-en-2- hydroperoxide (5a, 300 mg) and 2-Adamantanone (250 mg) in acetonitrile (20 ml) was added p-toluenesulfonic acid (30 mg) and was stirred for 1 h at r.t. The reaction mixture was worked up and concentrated. Crude product was purified by column chromatography on silica gel to furnish 320 mg (71.04% yield) of trioxane 9a, m.p. 94-96°C.
The above trioxane was also prepared using different reaction conditions. Table 3 gives the conditions used and the yields of the trioxane 9a.
TABLE 3

(Table Removed)
*EtOH was removed under reduced pressure after photooxygenation and replaced by CHCI3 in the second step before the addition of 2-Adamantanone.
EXAMPLE 7 ETHYL 3-HYDROXY-3-(4-BROMO[l,l-BIPHENYL]-4-YL)-BUTANOATE (COMPOUND 2b, FORMULA 2, X = Br)
To a refluxing mixture of 4-(4-bromophenyl)acetophenone (10 g), I2 (5mg) and Zn (4.9g) in benzene (100 ml) was added ethylbromoacetate (6.1 ml) dropwise during 45 minutes. The mixture was refluxed for 45 minutes and then cooled to room temperature. It was acidified with 10% HCl
(75 ml) and benzene layer was separated. Organic layer was washed with water, dried (Na2SOa)
and concentrated. Crude product was crystalliz
ed from hexane to furnish 8g of B-hydroxyester (2b). Mother liquor was purified by column
chromatography on silica gel to furnish 3.7 g of B-hydroxyester (2b). The combined yield of B-
hydroxyester (compound 2b, formula 2, X=Br) was 11.7 g (88.9%), m.p. 70°C.
ETHYL 3-(4-BROMO-[l,l-BIPHENYL]-4-YL)-BUT-2-ENOATE (COMPOUND 3b,
FORMULA 3, X= Br)
To a solution of ethyl 3-hydroxy-3-(4-bromo[l,l-Biphenyl]-4-yl)-butanoate (2b, 8.0g) in benzene (75 ml) was added p-toluenesulfonic acid (420 mg) and was refluxed for l h 15 minutes. The reaction mixture was cooled, neutralized with NaHC03 solution, diluted with water and organic layer was extracted. Organic layer was washed with water, dried (NaHC03) and concentrated. Crude product was purified by column chromatography on silica gel to furnish 5g (65.7% yield) of ethyl 3-hydroxy-3-(4-bromo[l,l-Biphenyl]-4-yl)-but-2-enoate (3b, formula 3, X=Br) m.p. 96-98°C.
3-(4-BROMO-[l,l -BIPHENYL]-4-YL)-2-BUTENOL (COMPOUND 4b, FORMULA 4, X = Br)
To an ice cooled slurry of LiAlH4 (2.0g) in dry ether (200 ml) was added a solution of ethyl 3-hydroxy-3-(4-bromo-[l,l-Biphenyl]-4-yl)-but-2-enoate (3b, 4.4g) in dry ether (100 ml) dropwise. The reaction mixture was stirred for 5 h at 0°C. The reaction mixture was quenched with water (5 ml). A solution of 10% NaOH (5 ml) was added and the ether layer was decanted. The precipitate was washed with ether and the combined ether extract was concentrated . The crude product was chromatographed on silica gel to give 2g (52.6% yield) of 3-(4-bromo-[l.l -Biphenyl]-4-yl)-2-butenol (4b, formula 4, X = Br) m.p. 145-148°C.
3-(4-BROMO-[l,l-BIPHENYLl-4YL)-l-HYDROXY-BUT-3-EN-2-HYDROPEROXIDE (COMPOUND 5b, FORMULA 5, X = Br)
A solution of 3-(4-bromo-[l,l-Biphenyl]-4-yl)-2-butenol (4b, 100 mg) and methylene blue (5 mg) in acetoriitrile (7 ml) and CH2CI2 (7 ml) was irradiation with a 250 watt tungston-halogen lamp at -6°C while oxygen was passed through the reaction mixture for 5 h. The crude product obtained by usual aqueous workup was crystallized from CH2CI2 to give 20 mg of hydroperoxide 5b. The filtrate was chromatographed on silica gel to give 40 mg of
hydroperoxide 5b. The combined yield of hydroperoxide (compound 5b, formula 5, X = Br) was 60 mg (55% yield).
3,3-DIMETHYL-6-[(4-BROMO-[l,l-BIPHENYL]-4-YL)- VINYL]-l,2,4-TRIOXANE (TRIOXANE 7ba, FORMULA 7, X = Br; R,, R2=CH3, CH3)
A solution of 3-(4-bromo-[l,l-Biphenyl]-4-yl)-2-butenol (4b, 350 mg) and methylene blue (2 mg) in acetone (40 ml) was photooxygenated at -10°C for 5 h. To the mixture was added p-toluenesulfonic acid (50 mg) and left at r.t. for 18 h and then concentrated. The crude product was purified by column chromatography to give 300 mg (69.7% yield) of trioxane 7ba m.p. 92-95°C.
EXAMPLE 8 3-ETHYL-3-METHLY-6-[(4-BROMO-[l,l-BIPHENYL]-4-YL)- VINYL]-l,2,4-TRIOXANE (TRIOXANE 7bb, FORMULA 7, X = Br; R,, R2=CH3, CH2CH3)
A solution of 3-(4-bromo-[l,l -Biphenyl]-4-yl)-2-butenol (4b, 500 mg) and methylene blue (5 mg) in CH3CN (40 ml) and CH2Cl2 was photooxygenated at -6°C for 3 h. To the mixture was added ethyl methyl ketone (3 ml) and p-toluenesulfonic acid (40 mg) and left at r.t. for 18 h. The reaction mixture was diluted with saturated NaHC03 solution (5 ml) and worked up as above and concentrated. The crude product was purified by column chromatography to give 240 mg (37.5% yield) of trioxane 7bb as a mixture of two stereoisomers which were further purified to furnish the more polar isomer, m.p. 72-74 °C and less polar isomer, m.p. 82-85°C.
EXAMPLE 9 3-[(4-BROMO-[l,l-BIPHENYLl-4-YL)-VINYL]-l,2,5-TRIOXASPIRO (5,5) UNDECANE (TRIOXANE 7bc, FORMULA 7, X = Br; R, R2=CH2CH2CH2CH2CH2-)
A solution of 3-(4-bromo-[l,l-Biphenyl]-4-yl)-2-butenol (4b, 500mg) and methylene blue (5 mg) in CH3CN (35 ml) and CH2C12 (35 ml) was photooxygenated at -6°C for 3.5 h. Cyclohexananone (1 ml) and p-toluene sulfonic acid (60 mg) were added and reaction mixture was left at r.t. for 18 h. The reaction mixture was diluted with saturated NaHC03 solution (5 ml) and worked up as above and concentrated. Crude product was purified by column chromotography JO furnish 320 mg (47% yield, based on allylic alcohol 4b, used) of trioxane 7bc, m.p. 118-120°C .
EXAMPLE 10 TRIOXANE 7bd,FQRMULA 7, X = Br, R, R2 = =-CH2.CH2-CH[C(CH3)2CH2CH3]-CH2.CH2.
A solution of 3-(4-bromo-[l,l-Biphenyl]-4yl)-2-butenol (4b, 500gm) and methylene blue (2 mg) in CH3CN (40 ml) and CH2C12 (40 ml) was photooxygenated at -6°C for 3 h. t-amyl
cyclohexanone (1.5 ml) and p-toluenesulfonic acid (50 mg) were added and reaction mixture was left at r.t. for 17h . The reaction mixture was worked up and concentrated. Crude product was purified by column chromatography to furnish 480 mg (60% yield, based on allylic alcohol,4b used) of trioxane 7bd m.p. 122-124°C
EXAMPLE 11 TRIOXANE 8b, FORMULA 8, X = Br
A solution of 3-(4-bromo-[l,l-Biphenyl]-4yl)-2-butenol (4b, 350 mg) and methylene blue (2 mg) in CH3CN (25 ml) and CH2Cl2 (25 ml) was photooxygenated at -6°C for 3h. Norcamphor (750 mg) and p-toluenesulfonic acid (50 mg) were added and the reaction mixture was stirred at r.t. for 18 h. The reaction mixture was worked up as above and concentrated. Crude product was purified by column chromatography on silica gel to furnish 300 mg (42.8% yield, based on allylic alcohol. 4b used) of trioxane 8b. m.p. 122-124°C.
EXAMPLE 12 TRIOXANE 9b, FORMULA 9, X = Br
A solution of 3-(4-bromo-[l,l-Biphenyl]-4yl)-2-butenol (4b, 500 mg) and methylene blue (2 mg) in CH3CN (40 ml) and CH2Cl2 (40 ml) was photoooxygenated at 5°C for 5 h. 2-Adamantanone (lg) and p-toluenesulfonic acid (60 mg) were added and reaction mixture was stirred for 30 minutes and then left at r.t. for 16 h. Reaction mixture was worked as above and concentrated. Crude product was purified by column chromatography to furnish 490 mg (63.6% yield, based on allyl alcohol 4b, used) of trioxane 9b mp 118°C.
EXAMPLE 13 ETHYL 3-(4-CHLORO-[l,l-BIPHENYL]-4-YL)-BUT-2-ENOATE (COMPOUND 3c, FORMULA 3, X= Cl)
To a refluxing mixture of 4-(4-chlorophenyl)acetophenone (8.46 g), l2 (5mg) and Zn (2.55g) in benzene (200 ml) was added ethylbromoacetate (4.35 ml) dropwise during 30 minutes. The mixture was refluxed for 2 h and then cooled to room temperature. It was acidified with 10% HCl (75 ml) and benzene layer was separated. Organic layer was washed with water, dried (Na2S04) and concentrated. Crude ß-hydroxyester (compound 2c, formula 2, X=C1) was used as such without purification for the preparation of ethyl 3-hydroxy-3-(4-chloro-[l,l -Biphenyl]-4-yl)-but-2-enoate as follows:
To a solution of crude ethyl 3-hydroxy-3-(4-chloro-[l,l-Biphenyl]-4-yl)-butanoate (2b) in benzene (200 ml) was added p-toluenesulfonic acid (3 gm) and was refluxed for 3h 30 minutes. The reaction mixture was cooled, neutralized with NaHCO3 solution, diluted with water and organic layer was extracted. Organic layer was washed with water, dried (NaHCO3) and concentrated. Crude product was purified by column chromatography on silica gel to furnish 5.27g (47.91% yield) of ethyl 3-hydroxy-3-(4-chloro-[l,l -Biphenyl]-4-yl)-but-2-enoate (3c. formula 3. X=Cl)m.p. 91-94°C.
3-(4-CHLORO-[l,l -BIPHENYL]-4-YL)-2-BUTENOL ( COMPOUND 4C, FORMULA 4, X = C1)
To an ice cooled slurry of LiAlH4 (1.4g) in dry ether (200 ml) was added a solution of ethyl 3-hydroxy-3-(4-chloro-[l,l-Biphenyl]-4-yl)-but-2-enoate (3c, 2.8g) in dry ether (50 ml) dropwise. The reaction mixture was stirred for 2 h at 0°C. The reaction mixture was quenched with water. A solution of 10% NaOH was added and the ether layer was decanted. The precipitate was washed with ether and the combined ether extract was concentrated . The crude product was chromatographed on silica gel to give 1.8g (75% yield) of 3-(4-chloro-[l,l-Biphenyl]-4-yl)-butenol (4c, formula 4, X = CI) m.p. 130-132°C.
3-(4-CHLORO-[l,l-BIPHENYL]-4YL)-l-HYDROXY-BUT-3-EN-2-HYDROPEROXIDE (COMPOUND 5c, FORMULA 5, X =C1)
A solution of 3-(4-chloro-[l,l-Biphenyl]-4-yl)-2-butenol (4c,lg) and methylene blue (40 mg) in acetonitrile (30ml) and CH3CN was irradiation with a 250 watt tungston-halogen lamp at 10°C while oxygen was passed through the reaction mixture for 5 h 30 minutes. Solid hydroperoxide separated during the reaction was filtered through cintered funnel to give 600 mg of hydroperoxide 5c. The filtrate was chromatographed on silica gel to give 260 mg of hydroperoxide 5c. The combined yield of hydroperoxide (compound 5c, formula 5. X =C1) was 860mg (76.7% yield).
8-[(4-CHLORO-[l,l-BIPHENYL]-4YL)VINYL]-6,7,10-TRIOXASPIRO (4,5) DECANE (TRIOXANE 7ca, FORMULA 7, X=C1, R,R2 =-CH2CH2CH2CH2-)
A solution of 3-(4-chloro-[l,l-Biphenyl]4yl)-2-butenol (4c, 500gm) and methylene blue (40 mg) in CH3CN (30 ml) was photooxygenated at 5°C for 5 h. Cyclopentanone (0.5 ml) and hydrochloric acid (5 drops) were added and reaction mixture was stirred at r.t. for 1.5h and then left at r.t for 48 h. The reaction mixture was concentrated. Crude product was purified by column
chromatography to furnish 230 mg (33.8% yield, based on allylic alcohol,4c used) of trioxane 7ca m.p. 105-107°C.
EXAMPLE 14 3-[(4-CHLORO-[l,l-BIPHENYL]-4-YL)-VINYL]-l,2,5-TRIOXASPIRO (5,5) UNDECANE (TRIOXANE 7bb , FORMULA 7, X = CI; R, R1CH2CH2CH2CH2CH2-)
A solution of 3-[(4-chloro-[l,l-Biphenyl]-4-yl)-2-butenol (4c, 500mg) and methylene blue (40 mg) in CH3CN (30 ml) was photooxygenated at 5°C for 5 h. Cyclohexananone (0.5 ml) and hydrochloric acid (5 drops) were added and reaction mixture was stirred at r.t. for 1.5h and then left at r.t for 24 h. The reaction mixture was concentrated. Crude product was purified by column chromotography to furnish 360 mg (50% yield, based on allylic alcohol 4c, used) of trioxane 7cb, m.p. 109-111°C.
EXAMPLE 15 TRIOXANE 8c, FORMULA 8, X = CI
To a solution of 3-(4-chloro[l,l-Biphenyl]-4yl)-l-hydroxy-but-3-en-2-hydroperoxide (5c, 500 mg) and norcamphor (500 mg) in chloroform (100 ml) was added cone. Hydrochloric acid (5 drops) and the reaction mixture was stirred at r.t. for 1 h and then left at r.t. for 18 h. The reaction mixture was worked up as above and concentrated. The crude product was purified by column chromatography followed by crystallization from hexane to furnish 420 mg (64.6% yield) of trioxane 8c, m.p. 144-146°C.
EXAMPLE 16 TRIOXANE 9c, FORMULA 9, X = CI
A solution of 3-(4-chloro-[l,l-Biphenyl]-4yl)-2-butenol (4c, 500 mg) and methylene blue (50 mg) in CH3CN (60 ml) was photoooxygenated at 5°C for 5 h. 2-Adamantanone (lg) and hydrochloric acid (5 drops) were added and reaction mixture was stirred at r.t. for 2h and then left at r.t for 16 h. The reaction mixture was worked up and concentrated. Crude product was purified by column chromotography to furnish 560 mg (69.14% yield, based on allylic alcohol 4c, used) of trioxane 9c, m.p. 112-115°C .
POLLOWING THE ABOVE PROCEDURE THE FOLLOWING TRIOXANES WERE PREPARED:
FOLLOWING THE ABOVE PROCEDURE THE FOLLOWING TRIOXANES WERE PREPARED :
(Table Removed)
ANTIMALARIAL ACTIVITY
The antimalarial activity of the test compounds was evaluated in rodent using multidrug
resistant strain of Plasmodium yoelii Nigeriensis in swiss mice.
General Procedure: Random bred swiss mice of either sex (20+2gm) were inoculated
intraperitoneally with lx105 P. yoelii (MDR) parasites on day zero. The treatment with test
compounds were administered to group of 5 mice each at different dose levels ranging between 24-
96 mg/kg/day. The treatment was administered via intramuscular route for 4 consecutive days (day
0-3).
Blood smears from experimental mice were observed on day 4 and 7, day 10 and thereafter at regular intervals till day 28 or death of the animal. The parasitaemia level on day 4 was compared with the vehicle control group and the present suppression of parasitaemia in treated groups was calculated.
For determining the curative dose of a compound the treated mice were observed till day 28. The dose at which no parasitaemia develop during the observation period has been reported as the curative dose. The anti-malarial data is summarized in table 4.
Table 4 : ANTIMALARIAL ACTIVITY OF TRIOXANES AGAINST P.yoelii IN MICE
(Table Removed)










We claim :
1. A process for the preparation of novel substituted 1,2,4-trioxanes useful as antimalarial agents of general formula 7 of the drawing accompanying the specification wherein X repreents hydrogen, halo groups selected from bromo and chloro, R1 and R2 represent hydrogen alkyl groups such as methyl, ethyl, propyl, decyl, aryl selected from phenyl or R1, R2 together represent part of a cyclic system such as cyclopentane, cyclohexane, substituted cyclohexanes, bicyclo (2.2.1) heptane, adamantane which comprises reacting aryl methyl kenone of formula 1 of the drawing accompanying the specification wherein X represents hydrogen, halo groups selected from bromo or chloro with haloacetate such as ethylbromoacetate or ethylchloroacetate and Zn in presence of catalytic amount of I2 in an aprotic solvent at a temperature ranging from room temperature to refluxing temperature to give p-hydroxyester of formula 2 of the drawing accompanying the specification wherein X has the same meaning as above, dehydrating the above said p-hydroxyester using a dehydrating catalyst in an aprotic solvent at a temperature ranging from room temperature to refluxing temperature to give a,p-unsaturated ester of the formula 3 of the drawing accompanying the specification wherein X has the same meaning as above, reducing the above said ester with a metal hydride in an ether solvent at a temperature ranging from 0°C to refluxing to obtain allylic alcohol of formula 4 of the drawing accompanying the specification wherein X has the same meaning as above, photoxygenating the above said allylic alcohol
sensitizer in an organic solvent such as herein described at a temperature ranging from -10°C to room temperatures to obtain p-hydroxyhydroperoxide of the formula 5 of the drawing accompanying the specification with an aldehyde/ketone of the general formula 6 of the drawing accompanying the specification wherein R1 and R2 represent hydrogen, alkyl group such as methyl, ethyl, propyl and decyl, aryl selected from phenyl, and part of a cyclic system selected from group consisting of cyclopentane, cyclohexane, bicyclo (2.2.1) heptane, adamantane, in presence of an acid catalyst in an aprotic organic solvent at a temperature ranging from 0°C to room temperature, isolating and purifying by known methods to furnish novel substituted 1,2,4-trioxanes.
2. A process as claimed in claim 1 wherein a,(3-hydroxyestec of formula 2 are prepared in an aprotic solvent selected from toluene, benzene, tetrahydrofuran.
3. A process as claimed in claims 1-2 wherein ,p-unsaturated ester are prepared in an aprotic solvent selected from CHCI3, CH2CI2, benzene, toluene.
4. A process as claimed in claims 1-3 wherein the dehydrating catalyst used is selected from acidic catalyst such as iodine, p-toluenesulfonic acid, sulphuric acid P205 cation exchanger such as amberlyst 15.
5. A process as claimed in claims 1-4 wherein metal hydride used is liAIH4 in an ether solvent selected from diethylether, tetrahydrofuran.
6. A process as claimed in claims 1-5 wherein organic solvent used for photooxygenation of allytic alcohols is CH2CI2, benzene, CH3CN methanol.
7. A process as claimed in claims 1-6 wherein the sensitizer used is a dye selected from methylene blue, rose Bengal, tetrahydropheny, porphirine.
8. A process as claimed in claims 1-7 wherein trioxane of formula 7 are prepared by condensation of p-hydroxy hydroperoxide of formula 5 with aldehyde/ketones of formula 6 in an organic solvent selected from CH2CI2, CH3CN, CHCI3, benzene.
9. A process as claimed in claims 1-8 wherein aldehyde or ketone used is acetone, ethyl methyl, ketone, methyl propyl ketone, decyl methyl ketone, benzaldehyde, cyclopentanone, cyclohexanone, 4-phenylcyclohexanone, 4-t-amylcyclohexanone, cycloheptanone, norcamphor, 2-adamantanone.
10. A process for the preparation of novel substituted 1,2,4-trioxanes useful as antimalarial agents substantially as herein described with reference to the examples and drawing accompanying the specification.


Documents:

297-del-2002-abstract.pdf

297-del-2002-claims.pdf

297-del-2002-correspondence-others.pdf

297-del-2002-correspondence-po.pdf

297-del-2002-description (complete).pdf

297-del-2002-drawings.pdf

297-del-2002-form-1.pdf

297-del-2002-form-2.pdf

297-del-2002-form-3.pdf

297-del-2002-form-4.pdf


Patent Number 195824
Indian Patent Application Number 297/DEL/2002
PG Journal Number 31/2009
Publication Date 31-Jul-2009
Grant Date 21-Apr-2006
Date of Filing 26-Mar-2002
Name of Patentee COUNCIL OF SCIENTIIFC AND INDUSTRIAL RESEARCH
Applicant Address RAFI MARG, NEW DELHI-110001, INDIA
Inventors:
# Inventor's Name Inventor's Address
1 CHANDAN SINGH CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226001, U.P., INDIA.
2 SUNIL KUMAR PURI CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226001, U.P., INDIA.
3 PALLAVI TIWARI CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE, LUCKNOW-226001, U.P., INDIA.
PCT International Classification Number A61P 33/06
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA